Immunosuppressive therapy after organ transplantation is essential for treatment or prevention of allograft rejection and long-term survival of grafts. Currently used immunosuppressants, such as calcineurin inhibitors, mTOR inhibitors, and purine or pyrimidine inhibitors generally provide adequate immunosuppression, but also cause a broad spectrum of unwanted systemic side effects (such as infection, organ toxicity, and metabolic disturbances) and drug-drug interactions.
Calcineurin inhibitors such as cyclosporine and tacrolimus (Tac) are widely used in immunosuppressive therapy in transplant recipients. For example, 94% of kidney transplant recipients receive a calcineurin inhibitor immunosuppressant immediately following transplantation (Naesens et al., Clin. J. Am. Soc. Nephrol. 4:481-508, 2009). However, the side effects of these drugs, particularly nephrotoxicity, cause substantial morbidity and ultimately limit long-term graft and patient survival.